Angiotensin II antagonists against disorders associated with impaired neuronal conduction velocity, especially diabetic neuropathy

ABSTRACT

This invention relates to the use of angiotensin II antagonists in treating or preventing the development of disease conditions associated with impaired neuronal conduction velocity, such as diabetic neuropathy, as well as their use in the manufacture of a medicament for use in such treatment. The invention also concerns pharmaceutical compositions containing an angiotensin II antagonist together with one or more other agents known to be of value in treating or preventing the development of disease conditions associated with impaired neuronal conduction velocity.

TECHNICAL FIELD

This invention relates to therapeutic agents and in particular to theuse of compounds having angiotensin II antagonist activity (hereinafter“AII antagonists”) for the treatment or prevention of disease conditionsassociated with impaired neuronal conduction velocity in warm-bloodedanimals including man. The invention also concerns the use of a compoundhaving AII antagonist activity in the production of a medicament for usein the treatment or prevention of disease conditions associated withimpaired neuronal conduction velocity. The invention further concerns amethod of treating or preventing disease conditions associated withimpaired neuronal conduction velocity by administration of an AIIantagonist to a warm blooded animal (including man).

BACKGROUND TO INVENTION

Impaired neuronal conduction velocity is a feature of nerve dysfunctioncommonly found, for example, in diabetic patients, and in diseaseconditions, such as alcoholic, toxic or compression neuropathy.Consequently an agent which prevents or reverses impairment of nerveconduction velocity may have a beneficial effect in the treatment orprevention of such medical conditions in which nerve conduction velocityis reduced, for example, diabetic neuropathy. We have now surprisinglydiscovered that impaired neuronal conduction velocity in a diabetic ratis significantly reversed by administration of an AII antagonist.

DISCLOSURE OF INVENTION

According to the invention there is provided a method of treating orpreventing the development of disease conditions associated withimpaired neuronal conduction velocity in a warm-blooded animal(including a human being) requiring such treatment which comprisesadministering to said animal a therapeutically effective amount of anAII antagonist, or a pharmaceutically acceptable salt thereof.

Typical AII antagonists useful in the invention include:

(a)2-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazoledescribed in European Patent Application (EPA), Publication No. 253310;

(b)2-butyl-3-(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridinedescribed in EPA, Publication No. 399731;

(c)5,7-dimethyl-2-ethyl-3-(2′-(tetrazol-5-yl)biphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridinedescribed in EPA, Publication No. 400974;

(d)1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl]-methyl-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid described in EPA, Publication No. 434249;

(e)2-ethyl-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinolinedescribed in EPA, Publication No. 412848; and

(f)2-ethyl-5,6,7,8-tetrahydro-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinolinedescribed in EPA, Publication No. 453210;

(g)5,7-diethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-onedescribed in EPA, Publication No. 516392; and

(h)5,7-diethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,3,4-tetrahydro-1,6-naphthyridin-2-onedescribed in EPA, Publication No. 516392;

and the pharmaceutically acceptable salts thereof.

Further AII antagonists include those described in EPA, Publication Nos.253310, 323841, 324377, 399731, 400974, 401030, 403158, 403159, 407102,407342, 409332, 411507, 411766, 412594, 412848, 415886, 419048, 420237,424317, 425921, 425211, 426021, 427463, 429257, 430709, 430300, 434249,432737, 434038, 435827, 437103, 438869, 442473, 443983, 443568, 445811,446062, 449699, 450566, 453210, 454511, 454831, 456442, 459136, 456442,456510, 461039, 461040, 465323, 465368, 467207, 467715, 468372, 468470,470543, 475206, 475898, 479479, 480204, 480659, 481448, 481614, 483683,485929, 487252, 487745, 488532, 490587, 490820, 492105, 497121, 497150,497516, 498721, 498722, 498723, 499414, 499415, 499416, 500297, 500409,501269, 501892, 502314, 502575, 502725, 503162, 503785, 503838, 504888,505098, 505111, 505893, 505954, 507594, 508393, 508445, 508723, 510812,510813, 511767, 511791, 512675, 512676, 512870, 513533, 513979, 514192,514193, 514197, 514198, 514216; 514217, 515265, 515357, 515535, 515546,515548, 516392, 517357, 517812, 518033, 518931, 520423, 520723, 520724,521768, 522038, 523141, 526001, 527534, and 528762. Other AIIantagonists include those disclosed in International Patent Application,Publication Nos. WO 91/00277, WO 91/00281, WO 91/11909, WO 91/11999, WO91/12001, WO 91/12002, WO 91/13063, 91/15209, WO 91/15479, WO 91/16313,WO 91/17148, WO 91/18888, WO 91/19697, WO 91/19715, WO 92/00067, WO92/00068, WO 92/00977, WO 92/02510, WO 92/04335, WO 92/04343, WO92/05161, WO 92/06081, WO 92/07834, WO 92/07852, WO 92/09278, WO92/09600, WO 92/10189, WO 92/11255, WO 92/14714, WO 92/16523, WO92/16552, WO 92/17469, WO 92/18092, WO 92/19211, WO 92/20651, WO92/20660, WO 92/20687, WO 92/21666, WO 92/22533, WO 93/00341, WO93/01177, WO 93/03018, WO 93/03033 and WO 93/03040. The contents of theaforesaid European and International Patent Applications are herebyincorporated by reference thereto.

Prior to the present invention, AII antagonists have been described ashaving use in, for example, the treatment of hypertension and congestiveheart failure. However there has been no suggestion that a compoundpossessing AII antagonist activity might be useful in treating orpreventing impaired nerve conduction velocity.

According to a further aspect of the invention there is provided the useof an AII antagonist, or a pharmaceutically acceptable salt thereof, forthe manufacture of a medicament for use in the treatment or preventionof the development of disease conditions associated with impairedneuronal conduction velocity.

According to a further aspect of the invention there is provided amethod of reversing impaired neuronal conduction velocity in awarm-blooded animal (including a human being) requiring such treatmentwhich comprises administering to said animal a therapeutically effectiveamount of a compound having AII antagonist activity, or apharmaceutically acceptable salt thereof.

According to a further aspect of the invention there is provided the useof a compound having AII antagonist activity, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for use inthe reversal of impaired neuronal conduction velocity.

According to a further aspect of the invention there is provided amethod of treating or preventing diabetic neuropathy in a warm-bloodedanimal (including a human being) requiring such treatment whichcomprises administering to said animal a therapeutically effectiveamount of a compound having AII antagonist activity, or apharmaceutically acceptable salt thereof.

According to a further aspect of the invention there is provided the useof a compound having AII antagonist activity, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for use inthe treatment or prevention of diabetic neuropathy.

Preferred AII antagonists for use in the invention include:

(i)2-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole;

(ii)2-ethyl-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]-quinoline;

(iii)2-ethyl-5,6,7,8-tetrahydro-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]quinoline;

(iv)5,7-diethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one;and

(v)5,7-diethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one;

and the pharmaceutically acceptable salts thereof.

A particularly preferred AII antagonist is compound (ii).

A preferred pharmaceutically acceptable salt of compound (i) is, forexample, an alkali metal salt, especially the potassium salt.

A preferred pharmaceutically acceptable salt of compound (ii), (iii),(iv) or (v) is, for example, an acid addition salt, especially thehydrochloride salt.

The AII antagonists and their pharmaceutically acceptable salts may beobtained, for example, by the methods given in the relevant publishedEuropean and International patent applications referred to above.

In use, an AII antagonist (or a pharmaceutically acceptable saltthereof) will generally be administered for its treatment or preventionof the development of impaired neuronal conduction velocity in awarm-blooded animal (including a human being) requiring such treatmentin the form of a conventional pharmaceutical composition, for example,as may be described in the relevant published European or Internationalpatent applications referred to above, and generally in a form suitablefor oral administration (e.g. as a tablet, capsule, suspension orsolution). It will be appreciated that an AII antagonist may beadministered together with one or more pharmaceutical agents known inthe general art to be of value in treating or preventing medicalconditions in which neuronal conduction velocity is reduced, such asdiabetic neuropathy. In the latter case a particularly suitablepharmaceutical agent may be, for example, an aldose reductase inhibitoror hypoglycaemic agent. The invention thus also includes pharmaceuticalcompositions (to include, for example, a combination preparation forsimultaneous, separate or sequential use) containing an AII antagonisttogether with one or more pharmaceutical agents known in the general artto be of value in treating or preventing the development of diseaseconditions associated with impaired neuronal conduction velocity.

In general, the AII antagonist (or a pharmaceutically acceptable saltthereof) will be administered to man so that, for example a daily oraldose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) ora daily parenteral dose of up to 5 mg/kg body weight (and preferably ofup to 1 mg/kg) is received, given in divided doses as necessary.However, it will be readily understood that it may be necessary to varythe dose of therapeutic agent administered in accordance with well knownmedical practice to take account of the nature and severity of theimpaired neuronal conduction velocity under treatment and the age,weight and sex of the patient receiving the treatment.

The effects of a representative compound for use in a method accordingto the invention are described in the following non-limiting example:

EXAMPLE 1

Using an analogous method to that described by Cameron et al inQuarterlty Journal of Experimental Physiology, 1989, 74, 917-926, maturemale rats were divided into non-diabetic animals (normal control group)and animals rendered diabetic (by administration of streptozotocin(40-45 mg/kg in 20 mmol/l sodium citrate buffer, pH 4.5, i.p.). Thediabetic animals were further divided into two groups. After one month,the motor nerve conduction velocities in one of the diabetic groups(diabetic control group 1) were measured in vivo between the sciaticnotch and the knee for motor branches supplying the gastrocnemius andtibialis anterior muscles of the calf using the procedures described byCameron et al (ibid) (further details of the procedures are given inExperimental Neurology, 1986, 92, 757-761). Sensory nerve conductionvelocity was also measured for diabetic control group 1 in the saphenousnerve between the groin and ankle (again using the method of Cameron etal (ibid)). The remaining group of diabetic animals was further dividedinto two groups. One of these groups was given daily2-ethyl-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinolinehydrochloride (Compound A; 50 mg/kg) by gavage, the other groupremaining untreated (diabetic control group 2). After a further month,motor and sensory nerve conduction velocities were obtained as beforefor both the treated group and diabetic control group 2. These valueswere compared with the corresponding nerve conduction velocities whichhad been obtained for the normal control group at the beginning of thestudy. The following nerve conduction velocities (NCV) were obtained inthe relevant sciatic branches and in the saphenous nerve:

Motor NCV Tibialis Sensory NCV Gastrocnemius Anterior Saphenous Group n(m/s) (m/s) (m/s) Normal control 20 65.4 ± 1.9 65.1 ± 1.9 59.3 ± 1.3Diabetic control Group 1 (1 month) 12 52.4 ± 1.8 51.0 ± 1.4 50.7 ± 1.0Group 2 (2 months) 20 50.7 ± 1.3 41.7 ± 2.2 52.1 ± 1.2 Diabetic + 1262.8 ± 0.9 60.3 ± 1.2 60.2 ± 1.1 Compound A (n = number of animals ingroup)

What is claimed is:
 1. A method of treating a disease conditionassociated with impaired neuronal conduction velocity in a warm-bloodedanimal requiring such treatment which comprises administering to saidanimal a neuronal conduction velocity enhancing effective amount of anangiotensin II antagonist, or a pharmaceutically acceptable saltthereof.
 2. A method of reversing impaired neuronal conduction velocityin a warm-blooded animal requiring such treatment which comprisesadministering to said animal a neuronal conduction velocity enhancingeffective amount of a compound having angiotensin II antagonistactivity, or a pharmaceutically acceptable salt thereof.
 3. A method oftreating diabetic neuropathy in a warm-blooded animal requiring suchtreatment which comprises administering to said animal a neuronalconduction velocity enhancing effective amount of a compound havingangiotensin II antagonist activity, or a pharmaceutically acceptablesalt thereof.
 4. A method as claimed in claim 1, 2 or 3 wherein the AIIantagonist is selected from: (a)2-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole;(b)2-butyl-3-(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridine;(c)5,7-dimethyl-2-ethyl-3-(2′-(tetrazol-5-yl)biphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridine;(d)1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl]-methyl-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid; (e)2-ethyl-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline;(f)2-ethyl-5,6,7,8-tetrahydro-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline;(g)5,7-diethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one;and (h)5,7-diethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one;or a pharmaceutically acceptable salt thereof.
 5. A method as claimed inclaim 1, 2 or 3 wherein the AII antagonist is2-ethyl-4-[(2′-(1H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-methoxy]quinoline,or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising an angiotensin II antagonist, or apharmaceutically acceptable salt thereof, together with one or morepharmaceutical agents selected from aldose reductase inhibitors andhypoglycaemic agents.